Surgeons rely on fluoroscopic imaging to track the placement of medical devices and implants in patients. This is especially challenging, however, when the devices are polymeric. Conventional polymers are not easily detected using physiologically relevant X-ray radiography because their radiopacity is similar to that of human tissue as a result of the similar C, H, O and N elemental composition. Polymeric biomaterials with enhanced radiopacity have been extensively studied in recent years due to their potential applications in implantable orthopedic, prostheses and vascular devices that remain visible to X-ray after implantation. The ability of an element to attenuate X-rays is correlated with the atomic number of the element to the fourth power. Hence, heavy atoms, including iodine, have been utilized to impart radiopacity into polymers and enhance X-ray contrast.
Most enhancement strategies focus on two methods to modify the radiopacity of polymers. The first is to make radiopaque blends by incorporating radiopaque additives such as inorganic salts of heavy elements (La2O3, BaO, BaSO4, SrO, ZrO2, Ta2O5/SiO2, or SrCO3), or organic compounds with heavy atoms (triphenyl bismuth, I4C2B10H8). The majority of commercial radiopaque polymeric medical implants currently available are prepared in this way because it is relatively easy to manufacture them using extrusion and molding, and the contrast can be controlled by adjusting the blending ratio. However, physical blending has been found to possess some significant drawbacks. It is difficult to achieve stable blend dispersions, and the limited compatibility of polymers with radiopaque additives can lead to contrast agent leakage, which can subsequently lead to a decrease in radiopacity and invoke unwanted biological responses and mechanical failures.
A second known method for enhancing contrast involves synthesizing polymers that possess covalently bonded heavy atoms. Monomers have been prepared containing covalently bonded iodine (4-IEMA) and terpolymerized 4-IEMA with 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Electron spectroscopy for chemical analysis (ESCA) demonstrated the stability of this iodinated polymer. In these methods, iodine is incorporated into poly(ether urethane) in a two-step condensation polymerization by using an iodine-containing diol. This iodinated poly(ether urethane) has high radiopacity, good thermal stability and was not cytotoxic. In addition, the preparation of iodinated and/or brominated derivatives of dihydroxy monomers and polymers with different structures have been demonstrated and these polymers have been found to be degradable and tissue-compatible. Iodine-modified poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (pI2DTEc) polymers synthesized using a monomer containing iodine atoms in the 3,5 position of the aromatic rings of tyrosine have also been reported.
Unfortunately, however, incorporation of iodine atoms into these polymers has been found to have a distinct influence on the mechanical and protein adsorption properties of the resulting polymers. Combinatorial methods have been used to determine the minimal amount of iodinated polymer needed to have sufficient X-ray contrast under a variety of translationally relevant imaging conditions. Such chemical modification introduces radiopacity intrinsically into polymers, but generates polymers lacking the necessary mechanical strength.
Amino acid-based poly(ester urea)s (PEUs) are finding use in a number of regenerative medicine applications due to their inherent synthetic flexibility, which results in tunable mechanical and degradation properties. The resulting polymers are semi-crystalline depending on the amino acid precursors, and the hydrogen bonding in the urea groups imparts the polymers with strong mechanical properties. The ester and urea bonds allow for both hydrolytic and enzymatic degradation. The final degradation byproducts are amino acids, small diol segments and CO2, which can be readily metabolized and/or removed by the body. Moreover, unlike the acidic degradation byproducts of polyesters, the carboxyl group in PEU is buffered by the urea linkages at each repeat unit. It is believed, therefore, that the lack of inflammation found in vivo with PEU polymers is due, at least in part, to the absence of localized acidification during and after PEU degradation. Further, histological analysis of PEUs has shown that they are nontoxic and are therefore excellent candidates for tissue engineering constructs. Significantly, PEUs are synthetically flexible in that there are 20 kinds of naturally occurring amino acids and a number of non-natural amino acids derivatives have been successfully used in a number of applications. These amino acids, along with the various diols commercially available, permit the synthesis of PEUs having vastly different properties.
PEUs can also be chemically modified with bioactive groups to initiate specific responses both in vitro and in vivo. Growth factors and peptides, including osteogenic growth peptide (OGP), have been used to crosslink PEUs in order to increase the mechanical properties and bioactivity of the resulting materials. (See, Stakleff, K. S.; Lin, F.; Callahan, L. A. S.; Wade, M. B.; Esterle, A.; Miller, J.; Graham, M.; Becker, M. L. Acta Biomater. 2013, 9, 5132-5142, the disclosure of which is incorporated herein by reference in its entirety.) Chemical modification of PEUs with pendant clickable groups in order to fabricate functional nanofibers has also been reported. (See, Lin, F.; Yu, J. Y.; Tang, W.; Zheng, J. K.; Xie, S. B.; Becker, M. L. Macromolecules 2013, 46, 9515-9525, the disclosure of which is incorporated herein by reference in its entirety.)
Unfortunately, however, these PEU materials also lack radiopacity. Therefore enhancing X-ray contrast is necessary to increase the translational potential of these materials. Contrast enables use of X-ray fluoroscopy to show the clinician the precise location of the devices in vivo effectively and efficiently. The level of contrast needed varies with a number of factors including X-ray flux, tissue coverage and location relative to bone and other internal structures. Minimizing chemical modifications can reduce the variance in the physical-chemical properties. As such, there is a fine balance between ensuring sufficient contrast in a material while minimizing physical property changes to the polymer.
Accordingly, what is needed in the art is an amino acid based poly(ester urea) polymer (and related methods of making and use) that is metal free, degradable, radiopaque and suitable for use in surgical implants and other medical devices used within the body of a patient.